Included as part of the "PRECAUTIONS" Section
Vulnerability To Opioid Overdose
After opioid detoxification, patients are likely to have reduced tolerance to opioids. VIVITROL
blocks the effects of exogenous opioids for approximately 28 days after administration.
However, as the blockade wanes and eventually dissipates completely, patients who have been
treated with VIVITROL may respond to lower doses of opioids than previously used, just as they
would have shortly after completing detoxification. This could result in potentially lifethreatening
opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the
patient uses previously tolerated doses of opioids. Cases of opioid overdose with fatal outcomes
have been reported in patients who used opioids at the end of a dosing interval, after missing a
scheduled dose, or after discontinuing treatment.
Patients should be alerted that they may be more sensitive to opioids, even at lower doses, after
VIVITROL treatment is discontinued, especially at the end of a dosing interval (i.e., near the end
of the month that VIVITROL was administered), or after a dose of VIVITROL is missed. It is
important that patients inform family members and the people closest to the patient of this
increased sensitivity to opioids and the risk of overdose [see PATIENT INFORMATION].
There is also the possibility that a patient who is treated with VIVITROL could overcome the
opioid blockade effect of VIVITROL. Although VIVITROL is a potent antagonist with a
prolonged pharmacological effect, the blockade produced by VIVITROL is surmountable. The
plasma concentration of exogenous opioids attained immediately following their acute
administration may be sufficient to overcome the competitive receptor blockade. This poses a
potential risk to individuals who attempt, on their own, to overcome the blockade by
administering large amounts of exogenous opioids. Any attempt by a patient to overcome the
antagonism by taking opioids is especially dangerous and may lead to life-threatening opioid
intoxication or fatal overdose. Patients should be told of the serious consequences of trying to
overcome the opioid blockade [see PATIENT INFORMATION].
Injection Site Reactions
VIVITROL injections may be followed by pain, tenderness, induration, swelling, erythema,
bruising, or pruritus; however, in some cases injection site reactions may be very severe. In the
clinical trials, one patient developed an area of induration that continued to enlarge after
4 weeks, with subsequent development of necrotic tissue that required surgical excision. In the
postmarketing period, additional cases of injection site reaction with features including
induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis, have been reported. Some
cases required surgical intervention, including debridement of necrotic tissue. Some cases
resulted in significant scarring. The reported cases occurred primarily in female patients.
VIVITROL is administered as an intramuscular gluteal injection, and inadvertent subcutaneous
injection of VIVITROL may increase the likelihood of severe injection site reactions. The
needles provided in the carton are customized needles. VIVITROL must not be injected using
any other needle. The needle lengths (either 1 1/2 or 2 inches) may not be adequate in every
patient because of body habitus. Body habitus should be assessed prior to each injection for each
patient to assure that the proper needle is selected and that the needle length is adequate for
intramuscular administration. For patients with a larger amount of subcutaneous tissue overlying
the gluteal muscle, the administering healthcare provider may utilize the supplied 2-inch needle
with needle protection device to help ensure that the injectate reaches the intramuscular mass.
For very lean patients, the 1 1/2-inch needle may be appropriate to prevent the needle contacting
the periosteum. Either needle may be used for patients with average body habitus. Healthcare
providers should ensure that the VIVITROL injection is given correctly, and should consider
alternate treatment for those patients whose body habitus precludes an intramuscular gluteal
injection with one of the provided needles.
Patients should be informed that any concerning injection site reactions should be brought to the
attention of the healthcare provider [see PATIENT INFORMATION]. Patients
exhibiting signs of abscess, cellulitis, necrosis, or extensive swelling should be evaluated by a
physician to determine if referral to a surgeon is warranted.
Precipitation Of Opioid Withdrawal
The symptoms of spontaneous opioid withdrawal (which are associated with the discontinuation
of opioid in a dependent individual) are uncomfortable, but they are not generally believed to be
severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly by the
administration of an opioid antagonist to an opioid-dependent patient, the resulting withdrawal
syndrome can be severe enough to require hospitalization. Review of postmarketing cases of
precipitated opioid withdrawal in association with naltrexone treatment has identified cases with
symptoms of withdrawal severe enough to require hospital admission, and in some cases,
management in the intensive care unit.
To prevent occurrence of precipitated withdrawal in patients dependent on opioids, or
exacerbation of a pre-existing subclinical withdrawal syndrome, opioid-dependent patients,
including those being treated for alcohol dependence, should be opioid-free (including tramadol)
before starting VIVITROL treatment. An opioid-free interval of a minimum of 7–10 days is
recommended for patients previously dependent on short-acting opioids. Patients transitioning
from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms
for as long as two weeks.
If a more rapid transition from agonist to antagonist therapy is deemed necessary and appropriate
by the healthcare provider, monitor the patient closely in an appropriate medical setting where
precipitated withdrawal can be managed.
In every case, healthcare providers should always be prepared to manage withdrawal
symptomatically with non-opioid medications because there is no completely reliable method for
determining whether a patient has had an adequate opioid-free period. A naloxone challenge test
may be helpful; however, a few case reports have indicated that patients may experience
precipitated withdrawal despite having a negative urine toxicology screen or tolerating a
naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment).
Patients should be made aware of the risks associated with precipitated withdrawal and
encouraged to give an accurate account of last opioid use. Patients treated for alcohol
dependence with VIVITROL should also be assessed for underlying opioid dependence and for
any recent use of opioids prior to initiation of treatment with VIVITROL. Precipitated opioid
withdrawal has been observed in alcohol-dependent patients in circumstances where the
prescriber had been unaware of the additional use of opioids or co-dependence on opioids.
Cases of hepatitis and clinically significant liver dysfunction were observed in association with
VIVITROL exposure during the clinical development program and in the postmarketing period.
Transient, asymptomatic hepatic transaminase elevations were also observed in the clinical trials
and postmarketing period. Although patients with clinically significant liver disease were not
systematically studied, clinical trials did include patients with asymptomatic viral hepatitis
infections. When patients presented with elevated transaminases, there were often other potential
causative or contributory etiologies identified, including pre-existing alcoholic liver disease,
hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs.
Although clinically significant liver dysfunction is not typically recognized as a manifestation of
opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae
including acute liver injury.
Patients should be warned of the risk of hepatic injury and advised to seek medical attention if
they experience symptoms of acute hepatitis. Use of VIVITROL should be discontinued in the
event of symptoms and/or signs of acute hepatitis.
Depression And Suicidality
Alcohol- and opioid-dependent patients, including those taking VIVITROL, should be monitored
for the development of depression or suicidal thinking. Families and caregivers of patients being
treated with VIVITROL should be alerted to the need to monitor patients for the emergence of
symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare
In controlled clinical trials of VIVITROL administered to adults with alcohol dependence,
adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were
infrequent overall, but were more common in patients treated with VIVITROL than in patients
treated with placebo (1% vs 0%). In some cases, the suicidal thoughts or behavior occurred after
study discontinuation, but were in the context of an episode of depression that began while the
patient was on study drug. Two completed suicides occurred, both involving patients treated with
Depression-related events associated with premature discontinuation of study drug were also
more common in patients treated with VIVITROL (~1%) than in placebo-treated patients (0%).
In the 24-week, placebo-controlled pivotal trial in 624 alcohol-dependent patients, adverse
events involving depressed mood were reported by 10% of patients treated with VIVITROL
380 mg, as compared to 5% of patients treated with placebo injections.
In an open-label, long-term safety study conducted in the US, adverse events of a suicidal nature
(depressed mood, suicidal ideation, suicide attempt) were reported by 5% of opioid-dependent
patients treated with VIVITROL 380 mg (n=101) and 10% of opioid-dependent patients treated
with oral naltrexone (n=20). In the 24-week, placebo-controlled pivotal trial that was conducted
in Russia in 250 opioid-dependent patients, adverse events involving depressed mood or suicidal
thinking were not reported by any patient in either treatment group (VIVITROL 380 mg or
When Reversal Of Vivitrol Blockade Is Required For Pain
In an emergency situation in patients receiving VIVITROL, suggestions for pain management
include regional analgesia or use of non-opioid analgesics. If opioid therapy is required as part of
anesthesia or analgesia, patients should be continuously monitored in an anesthesia care setting
by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid
therapy must be provided by individuals specifically trained in the use of anesthetic drugs and
the management of the respiratory effects of potent opioids, specifically the establishment and
maintenance of a patent airway and assisted ventilation.
Irrespective of the drug chosen to reverse VIVITROL blockade, the patient should be monitored
closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary
In clinical trials with VIVITROL, there was one diagnosed case and one suspected case of
eosinophilic pneumonia. Both cases required hospitalization, and resolved after treatment with
antibiotics and corticosteroids. Similar cases have been reported in postmarketing use. Should a
person receiving VIVITROL develop progressive dyspnea and hypoxemia, the diagnosis of
eosinophilic pneumonia should be considered [see ADVERSE REACTIONS]. Patients should be
warned of the risk of eosinophilic pneumonia, and advised to seek medical attention should they
develop symptoms of pneumonia. Clinicians should consider the possibility of eosinophilic
pneumonia in patients who do not respond to antibiotics.
Hypersensitivity Reactions Including Anaphylaxis
Cases of urticaria, angioedema, and anaphylaxis have been observed with use of VIVITROL in
the clinical trial setting and in postmarketing use. Patients should be warned of the risk of
hypersensitivity reactions, including anaphylaxis. In the event of a hypersensitivity reaction,
patients should be advised to seek immediate medical attention in a healthcare setting prepared to
treat anaphylaxis. The patient should not receive any further treatment with VIVITROL.
As with any intramuscular injection, VIVITROL should be administered with caution to patients
with thrombocytopenia or any coagulation disorder (e.g., hemophilia and severe hepatic failure).
Use of VIVITROL does not eliminate nor diminish alcohol withdrawal symptoms.
Interference With Laboratory Tests
VIVITROL may be cross-reactive with certain immunoassay methods for the detection of drugs
of abuse (specifically opioids) in urine. For further information, reference to the specific
immunoassay instructions is recommended.
Patient Counseling Information
Advise the patient to read the FDA-Approved patient labeling (Medication Guide).
Physicians should include the following issues in discussions with patients for whom they
- Advise patients that if they previously used opioids, they may be more sensitive to
lower doses of opioids and at risk of accidental overdose should they use opioids
when their next dose is due, if they miss a dose, or after VIVITROL treatment is
discontinued. It is important that patients inform family members and the people
closest to the patient of this increased sensitivity to opioids and the risk of overdose.
- Advise patients that because VIVITROL can block the effects of opioids, patients
will not perceive any effect if they attempt to self-administer heroin or any other
opioid drug in small doses while on VIVITROL. Further, emphasize that
administration of large doses of heroin or any other opioid to try to bypass the
blockade and get high while on VIVITROL may lead to serious injury, coma, or
- Inform patients on VIVITROL that they may not experience the expected effects
from opioid-containing analgesic, antidiarrheal, or antitussive medications.
- Advise patients that a reaction at the site of VIVITROL injection may occur.
Reactions include pain, tenderness, induration, swelling, erythema, bruising, or
pruritus. Serious injection site reactions including necrosis may occur. Some of these
injection site reactions have required surgery. Patients should receive their injection
from a healthcare provider qualified to administer the injection. Patients should be
advised to seek medical attention for worsening skin reactions.
- Advise patients that they should be off all opioids, including opioid-containing
medicines, for a minimum of 7 – 10 days before starting VIVITROL in order to avoid
precipitation of opioid withdrawal. Patients transitioning from buprenorphine or
methadone may be vulnerable to precipitation of withdrawal symptoms for as long as
two weeks. Ensure that patients understand that withdrawal precipitated by
administration of an opioid antagonist may be severe enough to require
hospitalization if they have not been opioid-free for an adequate period of time, and is
different from the experience of spontaneous withdrawal that occurs with
discontinuation of opioid in a dependent individual. Advise patients that they should
not take VIVITROL if they have any symptoms of opioid withdrawal. Advise all
patients, including those with alcohol dependence, that it is imperative to notify
healthcare providers of any recent use of opioids or any history of opioid dependence
before starting VIVITROL to avoid precipitation of opioid withdrawal.
- Advise patients that VIVITROL may cause liver injury. Patients should immediately
notify their physician if they develop symptoms and/or signs of liver disease.
- Advise patients that they may experience depression while taking VIVITROL. It is
important that patients inform family members and the people closest to the patient
that they are taking VIVITROL and that they should call a doctor right away should
they become depressed or experience symptoms of depression.
- Advise patients to carry documentation to alert medical personnel to the fact that they
are taking VIVITROL (naltrexone for extended-release injectable suspension). This
will help to ensure that patients obtain adequate medical treatment in an emergency.
- Advise patients that VIVITROL may cause an allergic pneumonia. Patients should
immediately notify their physician if they develop signs and symptoms of pneumonia,
including dyspnea, coughing, or wheezing.
- Advise patients that they should not take VIVITROL if they are allergic to
VIVITROL or any of the microsphere or diluent components.
- Advise patients that they may experience nausea following the initial injection of
VIVITROL. These episodes of nausea tend to be mild and subside within a few days
post-injection. Patients are less likely to experience nausea in subsequent injections.
Patients should be advised that they may also experience tiredness, headache,
vomiting, decreased appetite, painful joints and muscle cramps.
- Advise patients that because VIVITROL is an intramuscular injection and not an
implanted device, once VIVITROL is injected, it is not possible to remove it from the
- Advise patients that VIVITROL has been shown to treat alcohol and opioid
dependence only when used as part of a treatment program that includes counseling
- Advise patients that dizziness may occur with VIVITROL treatment, and they should
avoid driving or operating heavy machinery until they have determined how
VIVITROL affects them.
- Advise patients to notify their physician if they:
- become pregnant or intend to become pregnant during treatment with VIVITROL.
- are breast-feeding.
- experience respiratory symptoms such as dyspnea, coughing, or wheezing when
- experience any allergic reactions when taking VIVITROL.
- experience other unusual or significant side effects while on VIVITROL therapy.
Frequently Asked Questions About Administering Vivitrol:
Can I prepare the suspension prior to my patient’s arrival?
No. You may remove the carton from the refrigerator prior to the patient’s arrival, but once
the diluent is added to the VIVITROL microspheres, the dose should be mixed and the
suspension administered immediately. It is very important to use proper aseptic technique
when preparing the suspension [see DOSAGE AND ADMINISTRATION].
How much time do I have between preparing and administering the dose?
It is recommended that the suspension be administered immediately once the product has
been suspended and transferred into the syringe. If a few minutes’ delay occurs after
suspension but before transfer into the syringe [see DOSAGE AND ADMINISTRATION (2.5;
Figure D)], the vial can be inverted a few times to resuspend and then transferred into the
syringe for immediate use [see DOSAGE AND ADMINISTRATION].
Can I use needles other than those provided in the carton?
No. The needles in the carton are specially designed for administration of VIVITROL. Do
not make any substitutions for components of the carton [see DOSAGE AND ADMINISTRATION].
The suspension is milky white upon mixing with the diluent. Is this normal?
Yes. VIVITROL microspheres will form a milky suspension when mixed with the provided
diluent [see DOSAGE AND ADMINISTRATION].
What if a needle clog occurs during administration of the product?
If a clog occurs during administration, the needle should be withdrawn from the patient,
capped with the attached needle protection device, and replaced with the spare administration
needle. Gently push on the plunger until a bead of the suspension appears at the tip of the
needle. The remainder of the suspension should then be administered into an adjacent site in
the same gluteal region [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies have not been conducted with VIVITROL.
Carcinogenicity studies of oral naltrexone hydrochloride (administered via the diet) have been
conducted in rats and mice.
In a two-year carcinogenicity study in rats, there were small increases in the numbers of
testicular mesotheliomas in males and tumors of vascular origin in males and females. The
incidence of testicular mesothelioma in males given naltrexone at a dietary dose of 100
mg/kg/day (3-times the human exposure based on an AUC(0-28d) comparison) was 6%, compared
with a maximum historical incidence of 4%. The incidence of vascular tumors in males and
females given dietary doses of 100 mg/kg/day was 4% but only the incidence in females was
increased compared with a maximum historical control incidence of 2% (3 and 32 times the
human exposure based on an AUC(0-28d) comparison in males and females, respectively). There
was no evidence of carcinogenicity in a 2-year dietary study with naltrexone in male and female
mice (12 and 3 times the human exposure based on an AUC(0-28d) comparison, respectively). The
clinical significance of these findings is not known.
Naltrexone was negative in the following in vitro genotoxicity studies: bacterial
reverse mutation assay (Ames test), the heritable translocation assay, CHO cell sister chromatid
exchange assay, and the mouse lymphoma gene mutation assay. Naltrexone was also negative in
an in vivo mouse micronucleus assay. In contrast, naltrexone tested positive in the following
assays: Drosophila recessive lethal frequency assay, non-specific DNA damage in repair tests
with E. coli and WI-38 cells, and urinalysis for methylated histidine residues.
Impairment Of Fertility
Daily oral administration of naltrexone caused a significant increase in
pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (75 times the
human exposure based on an AUC(0-28d) comparison). There was no effect on male fertility at this
dose level (6 times the human exposure based on an AUC(0-28d) comparison). The relevance of
these observations to human fertility is not known.
Use In Specific Populations
The available data from published case series with VIVITROL use in pregnant women are
insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse
maternal or fetal outcomes. There are clinical considerations (see Clinical Considerations).
Reproduction and developmental animal studies have not been conducted for VIVITROL. Daily
oral administration of naltrexone to female rats and rabbits increased the incidence of early fetal
loss at exposures ≥ 11 times and ≥ 2 times the human exposure, respectively. Daily oral
administration of naltrexone to pregnant rats and rabbits during the period of organogenesis did
not induce malformation at exposures up to 175 times and 14 times the human exposure,
respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%,
Disease-associated maternal and embryo-fetal risk
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as
low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often
results in continued or relapsing illicit opioid use.
Published studies have demonstrated that alcohol is associated with fetal harm including growth
restriction, facial abnormalities, central nervous system abnormalities, behavioral disorders, and
impaired intellectual development.
Reproduction and developmental studies have not been conducted for VIVITROL. Studies with
naltrexone administered via the oral route have been conducted in pregnant rats and rabbits.
Daily oral administration of naltrexone has been shown to increase the incidence of early fetal
loss when given to rats at doses ≥30 mg/kg/day (11 times the human exposure based on an
AUC(0-28d) comparison) and to rabbits at oral doses ≥60 mg/kg/day (2 times the human exposure based on an AUC(0-28d) comparison).
Daily oral administration of naltrexone to rats and rabbits during the period of organogenesis did
not induce malformations at doses up to 200 mg/kg/day (175- and 14-times the human exposure
based on an AUC(0-28d) comparison, respectively).
Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk. There are no data
on the effects on the breastfed infant or the effects on milk production. The developmental health
benefits of breastfeeding should be considered along with the mother’s clinical need for
naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the
mother’s underlying maternal condition.
The safety and efficacy of VIVITROL have not been established in the pediatric population. The
pharmacokinetics of VIVITROL have not been evaluated in a pediatric population.
In trials of alcohol-dependent subjects, 2.6% (n=26) of subjects were >65 years of age, and one
patient was >75 years of age. Clinical studies of VIVITROL did not include sufficient numbers
of subjects age 65 and over to determine whether they respond differently from younger subjects.
No subjects over age 65 were included in studies of opioid-dependent subjects. The
pharmacokinetics of VIVITROL have not been evaluated in the geriatric population.
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions
to this drug may be greater in patients with impaired renal function. Because elderly patients are
more likely to have decreased renal function, it may be useful to monitor renal function.
Pharmacokinetics of VIVITROL are not altered in subjects with mild renal insufficiency
(creatinine clearance of 50-80 mL/min). Dose adjustment is not required in patients with mild
renal impairment. VIVITROL pharmacokinetics have not been evaluated in subjects with
moderate and severe renal insufficiency. Because naltrexone and its primary metabolite are
excreted primarily in the urine, caution is recommended in administering VIVITROL to patients
with moderate to severe renal impairment [see CLINICAL PHARMACOLOGY].
The pharmacokinetics of VIVITROL are not altered in subjects with mild to moderate hepatic
impairment (Groups A and B of the Child-Pugh classification). Dose adjustment is not required
in subjects with mild or moderate hepatic impairment. VIVITROL pharmacokinetics were not
evaluated in subjects with severe hepatic impairment [see CLINICAL PHARMACOLOGY].